Pharmacokinetics of haloperidol and fluphenazine decanoates in chronic schizophrenia

In a double-blind comparison of haloperidol decanoate and fluphenazine decanoate given 4-weekly for 60 weeks as maintenance therapy in 38 chronic schizophrenic in-patients, plasma haloperidol, fluphenazine and prolactin levels were measured at regular intervals by radioimmunoassay. After the first injection, the mean plasma haloperidol level was highest at week 1 and fell gradually towards week 4. Mean pre-dose haloperidol levels changed little after week 8. Results suggested an absorption half-life of 4 weeks, although, in three cases steady state was only achieved after 11 monthly injections. Steady state levels of both haloperidol and fluphenazine correlated highly with dose. In two subgroups observed at steady state, both drugs produced a biphasic pattern of plasma drug concentration between injections, a rapid rise on day 1 followed by stable elevated levels and a gradual return to pre-injection concentration by the end of week 4. In the fluphenazine subgroup there was a second peak on day 7 and a steeper decline, so that the mean area-under-curve in week 4 was 64% of that in week 1. Drug injections at steady state induced an increase in prolactin secretion in all of the fluphenazine sub-group and in half of those receiving haloperidol. Plasma prolactin changes resembled those for drug concentrations, but differences in times of peaks on day 1 resulted in weak correlations. Fluphenazine appeared more potent than haloperidol in provoking prolactin secretion.     

Plasma fluphenazine concentrations in outpatients receiving fluphenazine decanoate (Modecate)

Plasma fluphenazine concentrations were measured by neuroleptic radioreceptor assay in 17 outpatients receiving chronic treatment with intramuscular fluphenazine decanoate. The range of concentrations was 0.5–2.4 μg/L over the dosage range of 0.30–3.2 mg/d. Age, sex and smoking status had no influence on plasma fluphenazine concentrations, which were not correlated with dose (expressed as mg/kg/d). There was no significant correlation between plasma concentration and clinical status of the patients. No difference in plasma concentration between patients with extrapyramidal signs or tardive dyskinesia and those without signs were observed.     

The sulfoxidation of fluphenazine in schizophrenic patients maintained on fluphenazine decanoate

Highly sensitive radioimmunoassays were applied to study the sulfoxidation of fluphenazine in 30 schizophrenic patients maintained on either 5 mg or 25 mg fluphenazine decanoate by intramuscular injection every 14 days over a period of 6 months. The presence of the sulfoxide metabolite was detected in all but one of the patients, such that 97% of the 340 plasma samples analysed contained the metabolite. Interpatient variations in plasma levels of fluphenazine, fluphenazine sulfoxide, and in drug to metabolite plasma level ratios were several fold higher than the corresponding intrapatient variations at both dosages. There were statistically significant tendencies for mean plasma fluphenazine levels to rise and mean plasma sulfoxide levels to fall over the 6-month period of study among patients on the high dose, consistent with our previously reported observation that it takes 3–6 months to establish a steady state of fluphenazine with this dosage regimen. By contrast, there were no statistically significant changes in mean plasma levels of either fluphenazine or its sulfoxide in patients on the low dose. Nevertheless, there was a significant rise in fluphenazine to fluphenazine sulfoxide mean plasma level ratios in both dosage groups. It is difficult to assess the significance of the changes in the drug to metabolite ratios with time, since there are no kinetic data on the phase II metabolism (conjugation) of fluphenazine or fluphenazine sulfoxide. This study shows that sulfoxidation is an important major pathway in the metabolism of intramuscularly-administered fluphenazine, and implies that metabolic sites other than gut wall are also involved in the process.     

Pharmacokinetic and pharmacodynamic studies on high doses of fluphenazine

Six chronic schizophrenics — earlier refractory to recommended doses of neuroleptic drugs but eventually responding to 250 mg fluphenazine heptanoate weekly — participated in a pharmacokinetic study. Five out of the six patients showed rather constant steady state plasma fluphenazine values on a 250 mg depot weekly. After depot drug withdrawal, the single oral dose pharmacokinetics on 400 mg fluphenazine showed the same variations in C _max, t _max, t 1/2 and AUC as are observed when recommended doses of fluphenazine are used. We thus could not demonstrate any dose-dependent pharmacokinetics on high oral fluphenazine doses. In half the patients, a biphasic decay in the plasma concentration curve indicated at least two compartments. The patients were then studied for up to 2 years on 200–500 mg fluphenazine as a single daily dose. The fluphenazine plasma levels were rather constant in the individual patients during this period. The plasma prolactin values were related to the fluphenazine values even in the high value area, thus showing a persistent pharmacodynamic variation capacity. The clinical part of the study did not show any relevant findings. Offprint requests to: S.J. Dencker     

A randomized clinical trial of haloperidol decanoate and fluphenazine decanoate in the outpatient treatment of schizophrenia

We carried out an 8-month double-blind clinical trial comparing haloperidol decanoate with fluphenazine decanoate in the maintenance treatment of 72 schizophrenic outpatients. A parallel-groups design was used with stratification by sex and injection interval (2, 3, or 4 weeks). The initial injection interval was based on pretrial maintenance treatment with fluphenazine esters. The dosage equivalency of haloperidol decanoate (1.5 cc or 75 mg) to fluphenazine decanoate (1 cc or 25 mg) used was 3:1. This remained approximately the same throughout a 2-month titration period with a flexible dose regimen, and a further 6-month period with a fixed dose regimen. No statistically significant differences in therapeutic effect were found between the drugs. Both drugs had a similar profile for drug-induced parkinsonism, but there was a trend for differences in masking tardive dyskinesia. Haloperidol and prolactin plasma concentrations were well correlated with dosage, with the exception of haloperidol concentrations in patients receiving injections at 2-week intervals.     

Plasma prolactin and fluphenazine concentrations in patients receiving fluphenazine decanoate: stability over injection intervals

Plasma prolactin and fluphenazine concentrations were measured in a group of 17 patients (9 males, 8 females) with schizophrenia who were receiving chronic treatment with fluphenazine decanoate. Neither measure was significantly correlated with clinical effect, as measured by the Brief Psychiatric Rating Scale, at any of the 5 pre-injection times examined. None of the measures showed statistically significant (P greater than 0.05; MANOVA) variations with time. Neither measure showed a significant correlation with the dose (expressed as mg/kg) of fluphenazine. The implications of the study for monitoring chronic treatment of schizophrenia are discussed.     

Plasma fluphenazine levels by radioimmunoassay in schizophrenic patients treated with depot injections of fluphenazine decanoate

1 Using a radioimmunoassay, plasma fluphenazine (FPZ) concentrations were examined in 33 schizophrenic patients during 38 intervals between injections of FPZ decanoate. Doses ranged from 12.5 to 150 mg and intervals from 1 to 5 weeks. At least three blood samples were taken between injections from each subject; also in 26 subjects additional samples were taken during the first 24 h post-injection. 2 FPZ was measurable in all plasma samples. 3 Each injection was followed by a rapid rise in plasma FPZ concentration to a maximum at 1-8 h. The height of this peak varied considerably. Within the next 12-36 h plasma FPZ fell to a level slightly above that found before injection and then remained stable until the next injection, thus confirming the steady release of FPZ from the depot over this period. 4 For the group, dose and mean plasma FPZ levels correlated strongly. 5 Despite this, there was a four-fold variation in plasma FPZ concentration among subjects receiving the same dose. 6 The FPZ level on the last day of an interval between injections was a satisfactory estimate of the mean FPZ level for the interval. 7 In one subject examined in this way, a positive correlation was found (r = 0.76) between plasma FPZ (by radioimmunoassay) and plasma prolactin levels.     

Blood and plasma kinetics of cis(Z)-clopenthixol and fluphenazine in psychiatric patients after intramuscular injection of their decanoic esters

Whole blood and plasma concentrations of active neuroleptic drugs were measured in eight schizophrenic outpatients who had received cis(Z)-clopenthixol decanoate in Viscoleo or fluphenazine decanoate in sesame oil by intramuscular injection. Whole blood and plasma concentrations were very similar, though there was a slight tendency for blood concentrations to be higher than plasma concentrations. Maximum concentrations appeared at 1 week after administration of cis(Z)-clopenthixol decanoate, whereas the highest concentrations after fluphenazine decanoate were seen at the end of the 3-week dosage interval. Some between-individual variation and a limited within-individual variation was seen.     

Clinical and toxicological profile of fluphenazine decanoate in elderly chronic schizophrenia

Twenty elderly chronic schizophrenic inpatients of both sexes, age ranging from 60 to 73 years (mean age 63 +/- 0.81 years), diagnosed according to DSM III-R, were treated with fluphenazine decanoate, 12.5 mg intramuscularly, administered every 21 days for six months. Psychopathological features were assessed by means of the Brief Psychiatric Rating Scale at time 0 and then weekly. At 0, 6, 12, 24, 36, 48, 72h and 7, 14 and 21 days after each administration, extrapyramidal side-effects were evaluated using the Extrapyramidal Side-Effects Scale. Fluphenazine was significantly effective in treating symptoms such as emotional withdrawal, blunted affect, suspiciousness, thought disturbances, but not hallucinations. The most severe extrapyramidal side-effects occurred within the first two days of administration of fluphenazine, with a peak after 36 h, following the first four administrations of the drug, possibly related to early peak plasma concentrations. The severity of these effects was reduced after the fifth injection indicating the occurrence of tolerance mechanisms during long-term fluphenazine administration.     

Kinetics of oral fluphenazine disposition in humans by GC-MS

The disposition of fluphenazine was investigated in six healthy volunteers following oral administration (5 mg). Using a sensitive and specific GC-MS procedure plasma fluphenazine concentrations were measured up until 32 h after drug administration. Peak plasma concentrations varied widely (range: 0.26-1.06 ng/ml) and were observed at 2.8 +/- 0.5 h following fluphenazine administration. The apparent terminal elimination half-life of fluphenazine was 33.1 +/- 8.1 h. The area under the plasma concentration-time curve differed widely between subjects (range: 7.1-28.6 ng/ml h) suggesting large interindividual differences in the extent of fluphenazine presystemic elimination.     

Plasma levels of neuroleptic in patients receiving depot fluphenazine

Depot forms of fluphenazine are frequently used in the outpatient treatment of psychiatric patients. To gather relevant data on pharmacokinetic characteristics of depot fluphenazines, the authors measured plasma levels of neuroleptic activity in 76 clinic patients on stable dosage regimens of fluphenazine decanoate or fluphenazine enanthate. Dose and plasma neuroleptic activity level were highly correlated for both forms of depot fluphenazine. Furthermore, the slope of the regression of log dose to the log plasma neuroleptic activity was the same for both drug forms. However, doses of enanthate twice those of decanoate were associated with the same mean plasma level of neuroleptic activity. Finally, while blood levels of drug overlapped markedly in cohorts of patients receiving different doses of depot medication, the assumption of recent studies that, on the average, patients in such cohorts have different blood and tissue levels of drug was confirmed.     

Plasma levels of fluphenazine during fluphenazine decanoate treatment in schizophrenia

The authors measured plasma fluphenazine levels in 20 schizophrenic patients receiving 25 or 50 mg fluphenazine decanoate (FPZ-D) by IM injection every 2 weeks. The plasma levels were determined by a sensitive gas-liquid chromatographic (GLC) assay with a nitrogen detector device developed in their laboratory. Using this chemical assay method, they replicated the finding of a sharp initial plasma peak within 24 h after the injection followed by a low but rather stable plasma level as previously reported by nonchemical assay methods. The interval plasma levels (averages of day 4–10 after injection) ranged from 0.17–0.61 ng/ml in 10 patients who received 25 mg; and 0.20–0.93 ng/ml in 7 patients who received 50 mg FPZ-D every 2 weeks. This four-fold variation in plasma levels during FPZ-D injection was smaller than previously reported levels achieved with oral antipsychotic drug treatment. Based on the study of plasma levels achieved with FPZ-D injection and oral FPZ-H (fluphenazine HCl) in 6 patients, the dosage requirement of FPZ-D appeared to be difficult to predict from the oral dosage of FPZ-H in the same patient. Two weeks past injection, fluphenazine was undetectable in approximately half the samples with the GLC method. Thus, radioimmunoassay or radioreceptor assay, which also measures metabolites, might be more suitable for the study of plasma levels in patients receiving FPZ-D injection.     

An ultrasensitive method for the measurement of fluphenazine in plasma by high-performance liquid chromatography with coulometric detection

A new sensitive analytical method is described for the quantitation of fluphenazine in 1 ml plasma samples after low oral doses of this antipsychotic agent. The drug is isolated by a simple one step extraction technique and analyzed by high-performance liquid chromatography (HPLC) with coulometric detection. The limit of detection for fluphenazine was 10 pg/ml of plasma and standard curves from 25 to 1,000 pg/ml were linear with an overall coefficient of variation (CV) of less than 5%. The lowest quantifiable concentration of 25 pg/ml could be determined with a CV of 4.7%. The sensitivity of the HPLC assay was such that plasma concentrations of fluphenazine could be followed for 2 days following administration of a single 10 mg oral dose of fluphenazine dihydrochloride to healthy volunteers. Known metabolites of fluphenazine did not interfere in the assay as they eluted with retention times different from that of fluphenazine.     

Single-dose pharmacokinetics of fluphenazine after fluphenazine decanoate administration

Fluphenazine decanoate is commonly used as part of maintenance treatment of schizophrenia, but its pharmacokinetics are poorly understood. We administered a single intramuscular dose of fluphenazine decanoate to nine patients and found that plasma fluphenazine level did not decline to 50% of the peak level by day 26 in any of the patients. This means that it has a long half-life measurable in months rather than weeks.     

Kinetics of fluphenazine after fluphenazine dihydrochloride, enanthate and decanoate administration to man.

1 Fluphenazine (1,2-ethanol 14C) was administered to seven human subjects as the dihydrochloride and as the enanthate and decanoate esters. 2 The subjects had previously been treated with fluphenazine injections for at least 6 months. 3 Fluphenazine was separated from its radioactive metabolites by selective solvent extraction. Plasma concentrations were measured for up to 21 days after dosing. 4 The preparations showed differences in peak concentrations, times of the peaks and half-times of the elimination phase. The longest half-times occurred with the decanoate and the shortest with the dihydrochloride. 5 It is postulated that the differences in kinetics relate principally to the release of the compound from the site of injection. 6 There was no evidence for presence of the esters in plasma, urine or faeces.     

Plasma concentration of neuroleptic and serum prolactin in patients chronically receiving depot fluphenazine: No evidence of tolerance

The authors determined neuroleptic dose, plasma level of drug, and serum prolactin in 76 outpatients receiving depot fluphenazine. The patients had received neuroleptic treatment for periods ranging from 3 to 23 years (median 13 years). Plasma level of drug correlated with dose (r_s = 0·73, p>0·0001). Prolactin levels were linearly correlated with dose (r_s = 0·42, p = 0·0001) and plasma level of drug (r_s = 0·64, p>0·0001). There was a tendency for dose and, concomitantly, plasma level of drug, to decrease with age (r_s = ?0·29, p = 0·01, for each). However, dose, plasma level of drug adjusted for dose, and serum prolactin adjusted for plasma level of drug did not correlate with duration of treatment. Neither did any of these measures correlate with treatment duration when adjusted for age. The findings suggest that while older patients were given lower doses of medication, changes in the metabolism of fluphenazine or tolerance to its prolactin-elevating effects did not occur during extended treatment.     

Methods for study of fluphenazine kinetics in man.

Fluphenazine and its principal metabolites, fluphenazine sulphoxide, and 7-hydroxyfluphenazine were identified and quantified in human plasma, urine and faeces following intramuscular and oral administration of 14C-fluphenazine dihydrochloride. The presence of a conjugate fraction was also noted. Unmetabolized fluphenazine was selectively extracted into n-heptane. The metabolites were separated by solvent extraction into toluene. Conjugates were hydrolysed back to fluphenazine, fluphenazne sulphoxide and 7-hydroxyfluphenazine. Fluphenazine and fluphenazine conjugates were also measured in the urine of patients receiving long term non-radioactive fluphenazine decanoate therapy. The urinary excretion rate of the conjugate fraction was systematically related to the plasma concentration, regardless of urine flow rate or pH, providing a convenient method for the assessment of fluphenazine kinetics by urinary excretion studies not involving administration of labelled drug.     

Comparative study of the pharmacokinetics of zuclopenthixol decanoate and fluphenazine decanoate

Seventeen outpatients were treated with depot neuroleptics, zuclopenthixol decanoate in Viscoleo or fluphenazine decanoate in sesame oil, with dosage intervals of 3 weeks. During the 4th, 6th, and 8th dosage interval blood samples were drawn in oxalated tubes. Plasma concentrations of the active neuroleptic drugs, zuclopenthixol and fluphenazine, were determined by high performance liquid chromatography. The concentrations indicated some interindividual as well as intraindividual variations. For zuclopenthixol the maximum concentration was most often seen at day 7 after injection, whereas the kinetics of the fluphenazine concentrations was more variable. There was an indication of more fluctuation in the 4th dosage interval than in the 8th dosage interval, possibly due to the fact that steady state has not yet been achieved at the 4th dosage interval.     

Effects of alcohol on serum fluphenazine levels in stable chronic schizophrenics

Seven chronic schizophrenic patients, stable for over 12 months on maintenance fluphenazine decanoate, were administered 40 g of alcohol orally soon after their regular injection. Blood samples for estimation of serum neuroleptic and prolactin levels were collected at various intervals over a 12 h period. The procedure was repeated at their next regular injection but without alcohol. It was found that alcohol ingestion produced a significant drop in both serum neuroleptic and prolactin levels which persisted during the study period.     

Tolerance to fluphenazine and supersensitivity to apomorphine in central dopaminergic systems after chronic fluphenazine decanoate treatment

Summary Fluphenazine decanoate was administered chronically to rats on a schedule for which marked tolerance developed to acute fluphenazine effects on several parameters of dopaminergic neuronal function. DOPAC and HVA levels, indicators of dopaminergic activity, were quantitated in terminal areas of the mesocortical, mesolimbic and nigrostriatal systems. With this fluphenazine regimen tolerance developed not only in the nigrostriatal and mesolimbic but also in the mesocortical dopamine system to the elevation of metabolite levels induced by acute fluphenazine administration. Evidence was obtained that tolerance was functional rather than metabolic and was characterized by a large reduction in the accumulation of metabolites which normally follows a challenge dose of fluphenazine. Other experiments suggested that the results were not due to the effects of chronic fluophenazine on the noradrenergic innervation of the cortex and were not explained by altered catabolism or clearance of the dopamine metabolites. During withdrawal from chronic fluphenazine decanoate treatment supersensitivity to apomorphine developed in the striatum. The time courses of the disappearance of apomorphine supersensitivity and of the reversal of tolerance to a fluphenazine challenge were different.